Brown bear attacks on humans: a worldwide perspective.

The increasing trend of large carnivore attacks on humans not only raises human safety concerns but may also undermine large carnivore conservation efforts. Although rare, attacks by brown bears Ursus arctos are also on the rise and, although several studies have addressed this issue at local scales, information is lacking on a worldwide scale. Here, we investigated brown bear attacks (n = 664) on humans between 2000 and 2015 across most of the range inhabited by the species: North America (n = 183), Europe (n = 291), and East (n = 190). When the attacks occurred, half of the people were engaged in leisure activities and the main scenario was an encounter with a female with cubs. Attacks have increased significantly over time and were more frequent at high bear and low human population densities. There was no significant difference in the number of attacks between continents or between countries with different hunting practices. Understanding global patterns of bear attacks can help reduce dangerous encounters and, consequently, is crucial for informing wildlife managers and the public about appropriate measures to reduce this kind of conflicts in bear country.

Molecular detection of Bartonella spp. in deer ked pupae, adult keds and moose blood in Finland.

The deer ked (Lipoptena cervi) is a haematophagous ectoparasite of cervids that harbours haemotrophic Bartonella. A prerequisite for the vector competence of the deer ked is the vertical transmission of the pathogen from the mother to its progeny and transstadial transmission from pupa to winged adult. We screened 1154 pupae and 59 pools of winged adult deer keds from different areas in Finland for Bartonella DNA using PCR. Altogether 13 pupa samples and one winged adult deer ked were positive for the presence of Bartonella DNA. The amplified sequences were closely related to either B. schoenbuchensis or B. bovis. The same lineages were identified in eight blood samples collected from free-ranging moose. This is the first demonstration of Bartonella spp. DNA in a winged adult deer ked and, thus, evidence for potential transstadial transmission of Bartonella spp. in the species.

Experiments on the ectoparasitic deer ked that often attacks humans; preferences for body parts, colour and temperature.

The deer ked (Lipoptena cervi) can fail in its host search. Host search fails when an individual deer ked irreversibly accepts a host unsuitable for its reproduction (e.g. a human) and drops its wings. In northern Europe, the main host of the deer ked is the moose (Alces alces). The deer ked is increasingly causing serious problems for humans (for example, causing deer ked dermatitis) and is considered a threat for the recreational use of forests. The adult deer ked flies in early and mid-autumn to search for a host. Our aims were: (i) to study whether there are ways to avoid deer ked attacks by wearing particular clothing, and (ii) to evaluate deer ked host choice. Using human targets, we explored the cues the deer ked uses for host selection. We studied which part of the host body deer keds target and if body colour and temperature affect their choice. In our experiments, deer keds landed more on dark and red clothing than on white clothing. Moreover, deer keds mostly attacked the upper body parts and preferred the back side of the body over the front side. Finally, deer keds preferred the warmest areas of the host.

Safety and immunogenicity of a tetravalent group B streptococcal polysaccharide vaccine in healthy adults.

Proposed strategies for prevention of neonatal group B streptococcal (GBS) infection have included active immunization of pregnant women and passive immunization of high-risk infants with hyperimmune GBS globulin derived from vaccinated plasma donors. To explore the feasibility of a program for generating hyperimmune GBS globulin, we evaluated the safety and immunogenicity of a candidate multivalent GBS vaccine containing purified polysaccharide from types Ia, Ib, II, and III among subjects most likely to develop an immune response following vaccination, i.e. those with pre-existing antibody to GBS. Thirty volunteers prescreened for serum antibody to type III GBS were immunized with a single subcutaneous injection of vaccine containing either 10, 25, or 50 micrograms of each polysaccharide type (Group 1). An additional ten volunteers prescreened for antibody to type Ia were vaccinated with the 50 micrograms dose (Group 2). Vaccination was generally well tolerated with minor reactions occurring in 27% of subjects. Using a quantitative enzyme-linked immunosorbent assay (ELISA), the seroconversion rates (> or = fourfold rise) and geometric mean antibody concentration (GMC in microgram IgG ml-1) 6 weeks after vaccination in Group 1 to type Ia, II, and III were 33% (GMC 5.2), 17% (GMC 3.6), and 70% (GMC 43.4), respectively. Quantitative titers were not available for type Ib, but a fourfold rise in ELISA units was seen in 13% of subjects. In Group 2, seroconversion rates to type Ia and III were 90% (GMC 73.4) and 40% (GMC 22.2), respectively. No significant dose-response effect was detected. Combined analysis of Groups 1 and 2 demonstrated that subjects with prevaccination antibody concentrations > 2 micrograms IgG ml-1 had significantly higher type-specific antibody concentrations following vaccination compared with subjects possessing lower levels of antibody before immunization. We conclude that our tetravalent GBS polysaccharide vaccine is safe but only modestly immunogenic in healthy seropositive adults. More potent vaccines will be required for public health use.

Utility of various commercially available human immunodeficiency virus (HIV) antibody diagnostic kits for use in conjunction with efficacy trials of HIV-1 vaccines.

There is a need for human immunodeficiency virus (HIV) screening assays which will distinguish uninfected HIV vaccine recipients from HIV-infected individuals. Commercial screening kits were used to test serum samples from low- and high-risk participants in clinical trials before and after immunization with various recombinant HIV type 1 (HIV-1) envelope glycoprotein 120 (gp120) candidate vaccines. All kits were 100% sensitive in detecting HIV infection. Both Murex Single Use Diagnostic System and United Biomedical, Inc., HIV type 1 or 2 (HIV-1/2) enzyme immunoassay (EIA) kits, which detect antibodies to HIV-1 gp41, were 98 to 100% specific when used to screen baseline or recombinant gp120-vaccinated populations as vaccine-induced antibodies to gp120 were nonreactive in these tests. The Abbott HIVAB HIV-1 EIA (lysate of whole infected cells, reactive with anti-gp120 antibodies) gave high levels of reactivity due to vaccine-induced antibodies and a high baseline rate of false positives (12 of 83) among nonvaccinated high-risk volunteers. Assays containing only gp41 and p24 solid-phase components are compatible with gp120-based vaccines but are unlikely to be useful in a similar role for vaccines containing gp160, gp41, or gp120 plus p24 antigens. Efficacy trials must be designed in concert with available diagnostic screening assays to avoid problems caused by vaccine-induced seroconversion in high-risk populations.

A phase I-II study evaluating the murine anti-IL-2 receptor antibody 2A3 for treatment of acute graft-versus-host disease.

A murine IgG1 antibody specific for the IL-2-binding site on the human lymphocyte IL-2 receptor beta chain (CD25) was evaluated in 11 patients who developed acute graft-versus-host disease following allogeneic marrow transplantation. All patients had received cyclosporine and methotrexate for prophylaxis of GVHD, either alone (4 cases), or in combination with antithymocyte globulin (4 cases) or with prednisone (3 cases). Patients had developed GVHD at 7-53 days (median 12) after transplantation and had failed treatment with corticosteroids for 3-44 days (median 19). Residual GVHD was of grade II severity in 4 patients, grade III in 5 patients, and grade IV in 2 patients. Sequential patients received monoclonal antibody in escalating doses from 0.1 mg/kg/day to 1.0 mg/kg/day for 7 days. Side effects were fever, respiratory distress, hypertension, hypotension, and chills occurring in 11 of 72 (14%) antibody infusions. Trough antibody levels greater than 6 micrograms/ml were achieved in patients treated with 0.5 or 1.0 mg/kg/day. Four of eight evaluable patients had an IgM antibody response, and one had an IgG response to the murine immunoglobulin. Clinical response of GVHD was evaluated in 10 patients who received the entire course of the antibody treatment. Among 7 patients treated within 40 days from transplantation, one patient had a complete response in the skin as the only involved organ, and 3 patients had a partial response, 2 in the skin and one in the gastrointestinal tract. No responses were achieved with liver disease at anytime or in any organ in patients treated beyond 40 days after transplantation. Since administration of this antibody was well tolerated and some efficacy was observed in patients with acute GVHD treated early after transplantation, there is a rationale for testing this antibody as an agent for prophylaxis of GVHD.

Pharmacokinetics of rifabutin.

We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.

Phase I study of a murine monoclonal anti-lipid A antibody in bacteremic and nonbacteremic patients.

Nine patients with suspected gram-negative bacterial sepsis were studied to determine the safety, pharmacokinetics, and immunogenicity of XMMEN-0E5, a murine immunoglobulin M monoclonal antibody directed against the core lipid A region of bacterial endotoxin. Antibody was administered by single intravenous infusion of 1 to 4 h duration at doses ranging from 0.1 to 15 mg/kg. Five patients had positive blood cultures for gram-negative bacteria, one patient had Torulopsis septicemia, one patient had gram-negative bacterial meningitis, and two patients were culture negative. No evidence of antibody-mediated toxicity was observed at any dose level. The serum half-life of the antibody was approximately 10 h at doses of 0.1 to 7.5 mg/kg and approximately 18 h at a dose of 15 mg/kg. No apparent difference in clearance of antibody was observed between bacteremic and nonbacteremic patients. Human anti-mouse antibodies were detected in the sera of three evaluable patients that received doses equal to or greater than 2.0 mg/kg but not in patients that received lower doses of antibody. This study demonstrates that XMMEN-0E5 is well tolerated at doses from 0.1 to 15 mg/kg and may be immunogenic at doses of 2.0 mg/kg and above. Controlled trials to establish the efficacy of this antibody in the treatment of gram-negative bacteremia are indicated.

Toxicity and immunogenicity of monoclonal antimelanoma antibody-ricin A chain immunotoxin in rats.

This study was performed to assess the subacute toxicity and immunogenicity in rats of XOMAZYME-MEL, an antimelanoma monoclonal antibody-ricin A chain immunotoxin. Female Sprague-Dawley rats received 14 consecutive daily i.v. injections of XOMAZYME-MEL at doses of 5 mg/kg/day, 1 mg/kg/day, or normal saline. Animals from each dose group were sacrificed on days 8, 15, and 22. The low dose of immunotoxin was well tolerated and produced only minimal signs of toxicity. Side effects in animals receiving the high dose of immunotoxin consisted of transient weight loss, peripheral edema, leukocytosis, hypoalbuminemia, and mildly elevated liver function tests. Histological findings in these animals included cytoplasmic vacuolization of hepatocytes, focal myocardial and skeletal muscle degeneration, and renal deposits of proteinaceous casts. The administration of immunotoxin resulted in the appearance of anti-mouse and antiricin A chain immunoglobulin binding activity in the sera of treated animals. This study documents the systemic effect of the multiple-dose administration of a ricin A chain immunotoxin in rats.

Effect of cyclophosphamide on the immunogenicity of monoclonal antimelanoma antibody-ricin A chain immunotoxin in rats.

This study was performed to determine the effect of treatment with cyclophosphamide (CY) on the formation of antimurine and anti-ricin A chain antibodies in rats treated with a murine monoclonal antimelanoma antibody-ricin A chain immunotoxin (IT). Animals received treatment with either IT alone or IT plus CY. IT treatment consisted of daily IV injections at a dose of 1 mg/kg/day on days 0, 1, 2, 3, 4. CY treatment consisted of a 25 mg/kg IP dose on day -1 followed by daily IP doses of 5 mg/kg/day on days 0, 1, 2, 3, 4. Antibody binding activities in treated animals were measured by enzyme-linked immunosorbent assay and reported as optical density values. Rats treated with IT plus CY had lower binding activity on day 7 (0.09 vs 0.6; p = .02), day 14 (0.42 vs 1.22; p = .001), and day 21 (0.11 vs 1.3; p = .001) compared to rats treated with IT alone. Lower levels of anti-ricin A chain binding activity were observed in CY treated rats on day 14 (0.35 vs 1.25; p = .001), but not on day 7 or day 21. These results indicate that treatment with CY can abrogate the immune response to murine antibody and partially abrogate the immune response to ricin A chain.

Contrast nephropathy.

Contrast nephropathy is an adverse alteration in renal function induced by intravascular contrast media. Most cases involve transient asymptomatic episodes; yet a significant number involve oliguria and/or permanent renal damage. The incidence of contrast nephropathy in the general hospitalized population is about 5%, and is associated with preexisting renal insufficiency and diabetes mellitus. The incidence in patients with normal renal function is significantly lower - 0.6% following IVP and 2% following angiography. Angiography carries risks inherent to the technical problems of the procedure itself. Preexisting renal insufficiency is the most significant predisposing condition of contrast nephrotoxicity. As many as two-thirds of patients with chronic renal failure may experience an acute deterioration in renal function following exposure. Most of these episodes are transient and benign. Diabetic patients with preexisting renal insufficiency are at an even greater risk; about 75% of such patients will experience renal complications. The risk is even higher in JODM patients with severe renal disease; there is an over 90% incidence of nephrotoxicity with as many as half sustaining permanent renal damage. Adequate hydration does not appear to reduce the incidence of contrast nephropathy in susceptible patients, but it may reduce the likelihood of oliguria and permanent damage. In multiple myeloma the risk of contrast-induced renal failure is low, and probably involves a different pathogenesis than seen in other cases of contrast nephropathy. The incidence in myeloma patients is probably increased in the presence of dehydration and renal insufficiency. Peripheral vascular disease, hypertension, old age and large and repeated doses of contrast may increase the risk in susceptible patients. Prevention of contrast nephropathy must start with identification of patients at risk. In patients with preexisting renal insufficiency, and especially diabetic patients with preexisting renal insufficiency, the anticipated benefit should outweigh the potential risk of exposure to contrast media.

Intravenous pyelography in nonuremic diabetic patients.

We studied the influence of intravenous pyelography (IVP) in 40 diabetic patients with a serum creatinine level of less than 2 mg/100 ml. None of the patients experienced irreversible renal function changes but 4 patients had an early significant rise in creatinine levels (greater than 0.2 mg/100 ml). In 3 of these it was only mild, but 1 patient sustained reversible serious damage with a creatinine rising from 1.6 to 3.8 mg/100 ml. 3 of these 4 patients had evidence of renal disease with mild creatinine elevations or proteinuria. Thus, IVP is a relatively safe procedure in nonuremic diabetic patients. This is different from IVP in diabetic patients who have creatinines over 2 mg/100 ml where 76% of the patients have serious acute renal failure and this is irreversible in one-third.

Exacerbation of diabetic renal failure following intravenous pyelography.

Twenty-two of 29 (76 per cent) diabetic patients with a creatinine level of more than 2 mg/100 ml had exacerbation of renal failure following intravenous pyelography. In nine patients this was irreversible. Particularly at risk seem to be patients with early onset diabetes (less than 40 years), and those patients with severe renal failure (creatine over 5 mg/100 ml). No less that 15 of 16 (93 per cent) such patients had problems after intravenous pyelography; of these, nine (56 per cent) had irreversible deterioration. This report, in context with the increasing number of case reports of similar findin.gs, indicates that intravenous pyelography is dangerous in patients with juvenile onset diabetes who have a creatinine level of more than 5 mg/100 ml.